Conjugation of drugs to antibodies, either directly or via linkers, involves a consideration of a variety of factors, including the identity and location of the chemical group for conjugation of the drug, the mechanism of drug release, the structural elements providing drug release, and the structural modification to the released free drug. In addition, if the drug is to be released after antibody internalization, the mechanism of drug release must be consonant with the intracellular trafficking of the conjugate.
While a number of different drug classes have been tried for delivery via antibodies, only a few drug classes have proved efficacious as antibody drug conjugates, while having a suitable toxicity profile.
Tubulysins are a class of potent antimitotic agents isolated from myxobacteria (J. Antibiot. 2000, 53, 879). Tubulysins prevent the assembly of the tubulins into microtubulcs and have been evaluated as payloads for delivery as an ADC (US 2011/0027274 A1, WO2015/157592A1, WO14080251). However, there remains a need for additional tubulysins with improved properties.